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Hindawi Publishing CorporationInternational Journal of PediatricsVolume 2009, Article ID 427682, 6 pagesdoi:10.1155/2009/427682

Clinical Study

Sepsis-Related Mortality of Very Low Birth Weight BrazilianInfants: The Role of Pseudomonas aeruginosa

Sylvia Maria Porto Pereira,1, 2, 3, 4 Maria Helena Cabral de Almeida Cardoso,1

Ana Lucia Figuexeds,2, 4 Haroldo Mattos,4, 5 Ronaldo Rozembaum,6 Vanessa IsidoroFerreira,4, 7 Maria Antonieta Portinho,4, 7 Ana Cristina Goncalves,2

and Elaine Sobral da Costa3

1 Post-Graduate Department, Fernandes Figueira Institute, Rui Barbosa Avenue, 716, Flamengo, Rio de Janeiro 22250-020, Brazil2 Neonatology Department, Servidores do Estado Hospital, Sacadura Cabral Street 178, Saude, Rio de Janeiro 20221-903, Brazil3 Pediatrics Institute IPPMG Pediatrics Department, Federal University of Rio de Janeiro, Bruno Lobo Avenue, 50,Ilha do Fundao, Rio de Janeiro 21914 912, Brazil

4 Estacio De Sa University, Riachvelo Street 27-Centro, Riode Janeiro, CEP 20230-010, Brazil5 Epidemiology Department, Servidores do Estado Hospital, Sacadura Cabral Street 178, Saude, Rio de Janeiro 20221-903, Brazil6 Hospital Infection Control Department, Servidores do Estado Hospital, Sacadura Cabral Street 178, Saude,Rio de Janeiro 20221-903, Brazil

7 Medical Residence, Fernandes Figueira Institute, Rui Barbosa Avenue, 716, Flamengo, Rio de Janeiro 22250-020, Brazil

Correspondence should be addressed to Sylvia Maria Porto Pereira, [email protected]

Received 9 May 2009; Revised 29 September 2009; Accepted 23 December 2009

Recommended by Sunit C. Singhi

The aim of this study is to identify risk factors for sepsis-related mortality in low birth weight (<1500 g) infants. We performedretrospective cohort study to investigate risk factors for sepsis-related mortality in all neonates birth weight <1500 g admitted toLevel III neonatal intensive care unit, Brazil, April 2001/September 2004. Of the 203 cases, 71 (35%) had sepsis. Of those, gram-positive was identified in 52/87 blood cultures (59.8%), the most common Coagulase-negative Staphylococcus (31/87; 35.5%).Gram-negative was present in 29 of the 87 positive blood cultures (33.3%), with Pseudomonas aeruginosa (8/87; 9.1%), the mostfrequent agent. Overall 21 of 71 infants with sepsis (29.6%) died. Risk factors for sepsis-related mortality were gestational age≤28 weeks, birth weight ≤1000 g (9.6 times more often than birth weight >1000 g), five-minute Apgar ≤7, gram-negative sepsis,mechanical ventilation (6.7 times higher than no use), and intravascular catheter. Sepsis-related mortality was due, mainly, toPseudomonas aeruginosa; birth weight ≤1000 g and mechanical ventilation were strong sepsis-related mortality predictors.

Copyright © 2009 Sylvia Maria Porto Pereira et al. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

1. Introduction

Neonatal sepsis is a frequent complication of very low birthweight (VLBW) infants and it is an important cause ofneonatal morbidity and mortality [1, 2]. VLBW infantsdevelop 2.7 times more sepsis than other infants since theirimmune system and skin barrier are immature and theyare exposed to many invasive diagnostic and therapeuticprocedures [3]. Morbidity and mortality in a neonatalintensive care unit (NICU) can be reduced by knowledge ofthe epidemiology of the microbiology, infection rate profile

and antibiotic sensitivity, and by introducing practices thatare based on clinical evidence [4, 5]. Special attention mustbe given to infection by Pseudomonas aeruginosa due to ahigh mortality rate [6]. The aim of this study is to identifythe risk factors involved in the mortality caused by sepsisof a VLBW infants population with sepsis, in particular, therole of Pseudomonas aeruginosa, a very aggressive pathogen.The infants were hospitalized in the NICU of a high-riskmaternity in a tertiary-level public hospital specialized incaring for highly complex patients. Secondary objectives areto determine the frequency and distribution of the pathogens

2 International Journal of Pediatrics

that cause infection and to describe the characteristics of thispopulation.

2. Methods

2.1. Patients. All VLBW infants were born at the maternityof Servidores do Estado Hospital (SHE), Rio de Janeiro, RJ,Brazil and admitted in the NICU of the same hospital, justafter birth, between 1 April, 2001 and 30 September, 2004meeting the following criteria: birth weight (BW) <1500 g,clinical evidence of systemic infection and positive bloodculture result for bacterium or yeast on one or more bloodcultures obtained at any time while infants were inpatientsin the NICU. Infants died of nonsepsis causes, with lethalcongenital malformations and chromosomal abnormalitieswere excluded.

2.2. Chart Review. This retrospective cohort study collecteddata from the medical records of the selected VLBW infantsusing an investigation protocol. Relevant informationsincluded Antenatal and Intrapartum History: gestational age(GA) based on the date of the last menstruation, uterusfundus measurement, and ultrasonography performed until12 weeks of GA; time elapsed between rupture of membranesand birth; mode of birth; Apgar score at the first, fifth, andtenth minute of life; gender; BW; BW and GA relationshipaccording to Usher and McLean’s growth curves [7]. EventsRelated to Infection Episodes: incidence of sepsis, definedby the presence of clinical signs and symptoms as apnea,gastrointestinal problems, increased need for oxygen orventilatory support, and lethargy/hypotonic, and by oneor more positive blood cultures for bacterium or yeastobtained at any time during the infant’s stay at the NICU.Any organism, including Coagulase-negative Staphylococcus(CONS) was considered the caused agent of sepsis and not acontaminant if the criteria of the Vermont Oxford NetworkDatabase were present: clinical signs of sepsis, positive bloodculture for CONS, and intravenous antibacterial therapy forat least five days after obtaining blood culture or until death,in case it occurs within five days after obtaining blood culture[8]. Whenever CONS and another pathogen were identifiedin the same blood culture, only the other pathogen wasrecorded in the database, CONS was considered contaminantand this agent was discharged; age at the time of onset ofsepsis considered to be the day on which the first bloodculture for the event was positive: early-onset sepsis (EOS)defined as infection occurring before or at 72 hours oflife and late-onset sepsis (LOS), after 72 hours of life [9];organisms cultured and associated with death from sepsis;Neonatal Comorbidities: perinatal asphyxia defined as thepresence of five-minute Apgar score below six and signs ofencephalopathy as lethargy/stupor, hypotonia, and abnormalreflexes [10]; respiratory distress syndrome (RDS) definedas the need for oxigenotherapy, clinical features of RDS,and ventilation support and abnormal thorax radiographin the first 24 hours of life [3]; necrotizing enterocolitis(NEC) classified according to the system of Bell et al. [11];temperature instability, defined as temperature <36.5◦C or

>37.5◦C or a variation of >1◦C in a period of 24 hours andblood changes such as neutropenia, defined by a neutrophilcount < 1.5 × 103/L and thrombocytopenia, defined as aplatelet count < 80 × 103/L [11]. Therapeutic Interventions:use and length of use of intravascular catheter, defined asa peripherally inserted central catheter or by a vasculardissection and arterial or venous umbilical catheter, insertedbefore the onset of sepsis; use and length of use of mechanicalventilation and of total parenteral nutrition (TPN); timewhen enteral feeding was initiated and length of stay inthe NICU. Clinical Outcome: neonatal death was consideredrelated to infection when clinical signs and symptoms of sep-sis evolved to signs and symptoms of irreversible septic shockas systemic hypotension, acidemia, anuria, and hypoxia;and/or signs and symptoms of irreversible disseminatedintravascular coagulation syndrome as thrombocytopenia,major bleeding episodes as pulmonary hemorrhage, and,ultimately, progressing to death.

2.3. Statistical Analysis. Bivariate analysis was used to evalu-ate the association between potential risk factors and sepsis-related mortality. For statistical inference, the proportionswere compared with the chi-square test (χ2) or with Fisher’sexact test with Yates correction when the expected value inany cell of a 2 × 2 table is <5. P-value of .05 or less wasconsidered significant. The cut-off for continuous data wasobtained with the Receiver Operator Characteristics (ROC)curve. The cut-off was determined for the value with thehighest accuracy from the area of the ROC curve, it means, tothe highest area under the ROC curve. The odd ratios (ORs)were calculated with confidence intervals of 95% (CI95)for each risk factor. A stepwise backward unconditionalmultivariate logistic regression was performed to controlfor confounding and to assess the independence of theidentified risk factors. All variables with a P-value of .05 orless on bivariate analysis were included in the initial model.ORs and CI95 were calculated. The final model includedthe statistically significant variables in unconditional logisticregression analyzed by P-value of the test Walds. Statisticalanalysis was performed using the software Epi Info version3.3.2, SPSS version 12, and Epi Data version 3.1.

The study was reviewed and approved by the localResearch Ethics Committee (no. 000197).

3. Results

3.1. Incidence of Infection. Between 1 April, 2001 and 30September, 2004, 203 VLBW infants were admitted to theNICU of SEH, RJ. During their stay in the NICU, 71/203(35%) had one or more episodes of sepsis. For most VLBWinfants, 61/71 (86%), sepsis onset occurred after 72 hoursof life. Most of the VLBW infants, 55/71 (77.5%) had oneepisode; 11/71 (15.5%) two; 4/71 (5.6%) three; 1/71 (1.4%)four, totalling 87 episodes. A great number of the infectedneonates, 30/71 (42.3%) were BW ≤ 1000 g, classified asextreme low birth weight (ELBW) infants. The mean VLBWinfant’s age for all sepsis events was 12.9 (12.1) days, being9.8 (9.3) for the first and 26 (15.6) for the second episode.

International Journal of Pediatrics 3

Table 1: Number (%) of episodes of total sepsis, EOS and LOS in 71 VLBW infants testing positive for each organism, Servidores EstadoHospital, April 2001/September 2004.

ORGANISMTotal Sepsis EOS LOS

N % n % n %

Gram-positive organisms 52 59.8 10 11.6 42 48.2

Coagulase-negative Staphylococcus 31 35.5 7 8 24 27.5

Methicillin-sensible S. aureus 16 18.3 1 1.2 15 17.1

Methicillin-resistant S. aureus 1 1.2 — — 1 1.2

Enterococcus 2 2.4 — — 2 2.4

Streptococcus agalactiae (B) 1 1.2 1 1.2 — —

Listeria monocytogenes 1 1.2 1 1.2 — —

Gram-negative organisms 29 33.3 — — 29 33.3

Pseudomonas aeruginosa 8 9.1 — — 8 9.1

Klebsiella pneumoniae sp 6 6.9 — — 6 6.9

Acinetobacter calcoaceticus 6 6.9 — — 6 6.9

Unidentified gram-negative 3 3.4 — — 3 3.4

Serratia marcescens 3 3.4 — — 3 3.4

Enterobacter cloacae 2 2.4 — — 2 2.4

Escherichia coli 1 1.2 — — 1 1.2

Fungi 6 6.9 — — 6 6.9

Candida albicans 6 6.9 — — 6 6.9

Total 87 100 10 11.6 77 88.4

EOS: early-onset-sepsis.LOS: late-onset-sepsis.

3.2. Pathogen Distribution. The majority of infection events,either EOS or LOS, were due to gram-positive organisms,52/87 (59.8%). CONS was the most common pathogen ofall events (31/87; 35.5%) and among gram-positive events(31/52; 59.6%). Gram-negative organisms account for 29/87(33.3%) episodes, all LOS. P. aeruginosa was the mostcommon gram-negative pathogen (8/87; 9.1%), followed byKlebsiella sp. and Acinetobacter sp. Yeasts were found in 6/87(6.9%) episodes and Candida albicans was always the causingpathogen. The distribution of the organisms is shown inTable 1.

3.3. Antenatal, Intrapartum, and Neonatal History. Antenataland intrapartum history, neonatal comorbidities, and ther-apeutic interventions were reviewed. The continuous dataare presented as means and standard deviations and thecategorical data are presented as percentages (Table 2).

3.4. Sepsis-Related Mortality. Overall 21 of the 71 VLBWinfants with sepsis (29.6%) died, being 2/10 (20%) fromEOS, and 19/61 (32.7%) from LOS.

There were significant differences in death rates fromsepsis, depending on the organisms isolated from the lastpositive culture (Table 3). Episodes of sepsis with gram-negative organisms were more likely to result in death thanepisodes with gram-positive or fungus (13/29; 44.8% versus7/52; 13.4% versus 1/6; 16.7%; P < .05). Within this high-risk group, VLBW infants with P. aeruginosa sepsis were most

likely to die (6/8; 75% of infants with P. aeruginosa infectionsdied; P < .05).

ELBW infants (BW ≤ 1000 g) were significantly morelikely to die than those with BW > 1000 g (17/30; 56.7%versus 4/41; 9.7%; P < .05). The mean GA, BW, and five-minute Apgar score of VLBW infants who died were lowerthan that of those who survived (29.4 versus 32 weeks; 875versus 1130 g; 7.4 versus 8.4; P < .05 each one).

VLBW infants submitted to intravascular catheter andmechanical ventilation were significantly more likely to diethan those not submitted to these procedures (19/47; 40.4%versus 2/24; 8.3%; and 19/42; 45.26% versus 2/29; 6.9%;P < .05 each one). Enteral feeding onset before or at 72 hoursof life and length of stay were highly significant predictors ofsurvival (P < .05). The bivariate analysis is shown in Table 4.

3.5. Logistic Regression. The predictive model based ona stepwise backward unconditional multivariate logisticregression for 71 VLBW infants showed that BW indepen-dently contributed most to the dependent variable death,with a cut-off point of 1000 g. BW ≤1000 g infants presenteda sepsis-related mortality rate 9.6 times higher than BW >1000 g infants (P < .05). The use of mechanical ventilationpresented a clinically significant risk (sepsis-related mortalityrate 6.7 times higher) but the statistical significance wasmarginal (P = .05). Length of stay was statistically significantwith a negative coefficient, that is, the risk of death fromsepsis decreased as length of stay increased (P < .05). Thelogistic regression analysis is shown in Table 5.


Table 2: Risk factors for sepsis-related mortality in 71 VLBWinfants with sepsis, Servidores EstadoHospital, April 2001/September2004.

Risk factors: antenatal and intrapartum history,

neonatal comorbidities, therapeutic interventions

Continuous variables n %

Rupture of membranes at birth 55 77.5

<12 hours before birth 3 4.2

Caesarian section 53 74.6

Males 36 50.7

Birth weight ≤ 1000 g 30 42.3

Small for gestational age 45 63.4

Perinatal asphyxia 37 52.1

Respiratory distress syndrome 39 54.9

Necrotizing enterocolitis 12 16.9

Temperature instability 12 16.9

Neutropenia 14 19.7

Thrombocytopenia 44 61.9

Intravascular catheter 47 66.2

Total Parenteral nutrition 64 90.1

Mechanical ventilation 42 59.2

Enteral feeding onset > 72 hours 18 25.3

Categorical variables Mean Standarddeviation

Gestational age (weeks) 31 2.5

1-minute Apgar score 6.2 2.1

5-minute Apgar score 8.1 1.4

10-minute Apgar score 7.2 2

Birth weight (grams) 1054 232

Lenght of intravascular catheter (days) 10.37 8.7

Lenght of total parenteral nutrition (days) 9.12 7.52

Lenght of mechanical ventilation (days) 6.97 9.46

Length of stay (days) 53.8 35

4. Discussion

In our four-year cohort, sepsis was frequent, 35%, with thehighest risk of occurrence in the first two weeks of stay. Eventhought was caused mainly by gram-positive organisms,represented by CONS, the mortality was higher when causedby gram-negative organisms, particularly P. aeruginosa.Neonatal sepsis-related mortality rate was high, 29.6%, inmost cases involving ELBW infants, 56.7%, and due to gram-negative organisms, 44.8%, especially P. aeruginosa, 75%.The number of VLBW infants studied was low, however,representative of the whole population of neonates withBW < 1500 g assisted in a NICU of a reference center forhigh-risk pregnant women, during the selected period. Beinga retrospective study, there was a lack of comprehensiveinformation about risk factors. For this reason, the possiblerisk factors of sepsis-related mortality were reported underChart Review and included characteristics of the VLBWinfants population and events related to infection episodes.

There was a predominance of gram-positive organismsin EOS, especially CONS. This finding differs from thereports of Stoll et al. [9] and Rønnestad et al. [12] that, inthe recent years, there was a change in the profile of thepathogens causing EOS in NICU, with increase of gram-negative organisms, especially Escherichia coli. The incidenceof EOS due to Group B Streptococcus (GBS) was low, asingle episode, probably because, in most cases the evaluatedVLBW infants were product of the interruption of a high-riskpregnancy by caesarian section with ruptured of amnioticmembranes at birth. According to Hickman et al. [13],these two factors contribute to the decrease of the verticaltransmission of GBS and the lowest occurrence of EOS dueto this agent, as in our study.

There was a predominance of gram-positive organismsin LOS, 48.2%, mainly CONS, 27.5%. Costa et al. [14] inPortugal, Khashu [15] in Canada, Sarkar et al. [16] in theUnited State of America, and Richards et al. [17] in Colombiareported similar findings, what demonstrates that theseorganisms are prevalent agents of LOS in different countriesand continents. P. aeruginosa was the most frequent agent ofLOS, 9.1%, among gram-negative organisms. In contrast toour findings, Afroza [1] and Trotman and Bell [5] reportedK. pneumoniae as the most usual infectious agent amonggram-negative organisms in LOS. The reason for the highincidence of P. aeruginosa in our population must be objectof future studies.

The sepsis-related mortality rate of VLBW infants washigh, 29.6%, when compared to the rates reported in theliterature, 17.3% to 21% [5, 6, 17]. VLBW infants withgram-negative sepsis were at the greatest risk of death,44.8%. P. aeruginosa was the most aggressive agent of sepsis,responsible for the highest sepsis-related mortality rate, 75%,as reported by studies of Gordon and Isaacs [6].

BW ≤ 1000 g was identified by logistic regression asthe strongest independent sepsis-related mortality predictor.ELBW infants, a great vulnerable population to neonatalcomplications, presented the highest sepsis-related mortalityrate, 56.6%. Afroza [1] related that, among many risk factorsfor infection, the single most important factor is low birthweight, as we observed. This finding suggests that effortsto reduce neonatal sepsis-related mortality must be turnedespecially to this population.

The use of mechanical ventilation was identified bylogistic regression as a strong independent sepsis-relatedmortality predictor, which is in agreement with Flidel-Rimonet al. [18] and Stoll et al. [19]. This may be caused by the factthat neonates who need ventilation are the sickest patients,but also may be in part related to preventable ventilator-associated infection.

Enteral feeding initiated before or at 72 hours of life wasa predictor of survival. Our findings suggest the practice ofearly onset of feeding, and of the discerning indication andmaintenance of invasive procedures directed to the treatmentof VLBW infants to control sepsis-related mortality in thispopulation.

In summary, sepsis-related mortality is very high in lowbirth weight infants, mainly in extreme low birth infants.This is particularly true for patients with positive blood

International Journal of Pediatrics 5

Table 3: Number (%) of organisms related to total sepsis, EOS and LOS in 21VLBW infants who died of sepsis, Servidores do Estado Hospital,April 2001/September 2004.

Sepsis-related mortality

OrganismTotal sepsis EOS LOS

N n % n % n %

Gram-positive organism 52 7 13.4 1 1.9 6 11.5

Coagulase-negative staphylococcus 31 4 12.9 1 3.2 3 9.6

Staphylococcus aureus 16 2 12.9 —– —– 2 12.5

Staphylococcus MRSA 1 1 100 —– —– 1 100

Others 4 —– —– —– —– —– —–

Gram-negative organism 29 13 44.8 1 3.4 12 41.4

Pseudomonas aeruginosa 8 6 75 —– 6 75

Klebsiella pneumoniae sp 6 4 66.7 —– —– 4 66.7

Serratia 3 2 66.7 1 33.3 1 33.3

Escherichia coli 1 1 100 1 100

Others 11 —– —– —– —– —– —–

Fungi 6 1 16.7 —– —– 1 16.7

Candida albicans 6 1 16.7 —– —– 1 16.7

Total 87∗ 21∗∗ 2 19∗Total episodes sepsis-causing organisms∗∗Organisms that caused the last sepsis episode right before death of the 21 VLBW infantsEOS: early-onset-sepsis.LOS: late-onset-sepsis.

Table 4: Risk factors associated with sepsis-related mortality and sepsis relate survival of 71 VLBW infants with sepsis, Servidores EstadoHospital, April 2001/September 2004.

Risk factor OR CI 95 P

Sepsis-related mortality

Gestational age ≤ 28 weeks 14.67 2.12–116.07 .000

Birth weight ≤ 1000 g 10.93 2.76–47.15 .000

5th minute Apgar ≤ 7 5.41 0.75–47.61 .064 (Fisher)

Gram-negative organisms 2.91 1.14–7.45 .023

Use of mechanical ventilation 11.05 2.34–53.04 .003

Use of intravascular catheter 3.11 1.08–8.93 .003

Sepsis-related survival

Enteral feeding onset ≤ 72 hours 0.10 0.00–0.79 .022

OR = odds ratioIC 95 = 95% confidence interval.

Table 5: Risk factors for mortality and for survival in the 71VLBW infants with sepsis, identified by predictive model based on a backwardstep-by-step unconditional multivariate logistic regression.

Risk Factor OR CI95 P

Step 1(a) Length of stay 0.933 0.900–0.967 .000

Step 2(b)Length of stay >33 days 0.938 0.905–0.972 .000

Birth weight ≤1000 g 13.232 2.603–67.249 .002

Step 3(c)Mechanical ventilation 6.726 1.043–43.363 .045

Length of stay >28 days 0.944 0.912–0.978 .001

Birth weight ≤1000 g 9.600 1.702–54.156 .010

Odds ratio (OR) for the probability of death by sepsisIC95 = 95% confidence interval.(a) variable used in step 1 length of stay >28 days(b) variable used in step 2 birth weight ≤1000 g.(c) variable used in step 3 mechanical ventilationR2 = 0.685.


cultures due to P. aeruginosa. Attention to the control ofprematurity, knowledge of the neonatal flora and antibioticsensitivity profile, introduction of early nutritional supportwith early onset enteral feeding and efforts to decreaseventilator related events may play a role in decreasingthe mortality and morbidity of this very serious dis-ease.

Acknowledgments

The authors thank Professor Eduardo Fernandes, MD, Chiefof Urology, Veterans Hospital, Associate Professor, Universityof Minnesota, for the review of the English grammar. Theauthors thank the Hospital Infection Control Departmentof SEH for assistance in finding the data. The patients’parents gave their informed consent prior to the inclusionin the study. Its publication has been approved for allcoauthors, as well as, tacitly or explicitly, by the responsibleauthorities at the institution where the work has carried outat Servidores do Estado Hospital and Fernandes FigueiraInstitute, Rio de Janeiro, RJ, Brasil. The authors Sylvia MariaPorto Pereira, Maria Helena Cabral de Almeida Cardoso,Haroldo Mattos, Ronaldo Rozembaum, Vanessa IsidoroFerreira, Maria Antonieta Portinho, Ana Cristina Goncalvesand Elaine Sobral da Costa have declared no potentialconflict of interes.

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[17] C. Richards, J. Alonso-Echanove, Y. Caicedo, and W. R.Jarvis, “Klebsiella pneumoniae bloodstream infections amongneonates in a high-risk nursery in Cali, Colombia,” InfectionControl and Hospital Epidemiology, vol. 25, no. 3, pp. 221–225,2004.

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